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Novel 99mTc(III) Complexes as SPECT Radiotracers for MPI

新型 99mTc(III) 复合物作为 MPI 的 SPECT 放射性示踪剂

基本信息

批准号：
8680234
负责人：
SHUANG LIU
金额：
$ 22.41万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8680234
关键词：
American Animals Area Arts Biodistribution Biological Assay Blood Blood flow Boronic Acids Cardiac Cardiology Cardiovascular Diseases Cessation of life Chemistry Clinical Complex Coronary Arteriosclerosis Coronary heart disease Defect Detection Development Diagnosis Diagnostic Disease Educational process of instructing Electron Transport Complex III Equilibrium Evaluation Event Funding Future Goals Heart Hydrolysis Image In Vitro Ischemia Lead Length Life Ligands Literature Liver Myocardial Myocardial Infarction Myocardial perfusion Nuclear Patients Perfusion Positron-Emission Tomography Property Publications Radioactivity Radiochemistry Regimen Research Design Risk Sprague-Dawley Rats Structure Technetium Technetium Tc 99m Sestamibi Testing Therapeutic Time adduct clinical application clinically significant design experience improved in vivo lipophilicity meetings member novel prevent public health relevance radiotracer residence single photon emission computed tomography technetium Tc 99m 1,2-bis(bis(2-ethoxyethyl)phosphino)ethane uptake

项目摘要

DESCRIPTION (provided by applicant): In this project, we will evaluate 8 novel 99mTc(III) complexes [99mTc(S-R)(CDO)(CDOH)2B-Me] (R = P1 - P24) as SPECT radiotracers myocardial perfusion imaging. Sprague-Dawley (SD) rats will be used to evaluate their heart uptake and biodistribution. These studies are designed to answer the following three fundamental questions: (1) Are they able to localize and retain in heart (high heart uptake and long myocardial retention)? (2) What is the impact of PEG groups on heart uptake and liver clearance of 99mTc radiotracers? (3) Which is the best radiotracer with respect to the heart uptake, myocardial retention and heart/liver ratios? The main objective of this project is to increase the myocardial retention and minimize liver uptake of novel 99mTc(III) radiotracers while maintaining their high heart uptake. Hypothesis and Strategy: We hypothesize that thiolates are able to increase the myocardial retention of their 99mTc(III) complexes [99mTc(S-R)(CDO)(CDOH)2BMe] (R = P1 - P24) by preventing their hydrolysis in vivo because thiolate-S forms a stronger bond with Tc(III) than Cl. We also hypothesize that polyether groups will increase the myocardial retention and liver clearance of 99mTc(III) complexes since it has been well-established that PEG groups can increase the blood retention times of therapeutics, and our studies clearly showed that polyether groups are able to improve liver clearance of cationic 99mTc radiotracers. To test these hypotheses, we developed a two-step strategy. In first step, we will prepare complexes [99mTc(S-R)(CDO)(CDOH)2B-Me] (R = P1 - P24). Different R groups are used to balance their lipophilicity so that their heart uptake and T/B ratios can be optimized in a systematic fashion. In the second step, we will evaluate their heart uptake and biodistribution in SD rats. 99mTc-Teboroxime will be always used as the control for comparison purposes. The results from these studies will allow us to select an optimal candidate for further evaluations in the future. Clinical Significance. More than 70 million Americans currently live with cardiovascular diseases, which lead to >910,000 deaths each year. Rapid and accurate diagnosis in CAD patients is highly desirable so that appropriate therapeutic regimens can be given. Funding and successful completion of this project may lead to new 99mTc radiotracers that have very high first-pass extraction fraction with the heart/liver ratios much better than tha of 99mTc-Teboroxime. High heart uptake with better heart/liver ratios will allow for early acquisition of images, and improve the image quality by reducing scatter from liver radioactivity. High first-pass extraction and linear relationship between the blood flow rate and the radiotracer myocardial uptake will permit better detection of the presence and extent of coronary disease, and more precise delineation of myocardial perfusion defects, which is of considerable benefit in management of patients with known or suspected CAD and assessing risk of future cardiac events, particularly myocardial infarction and death.

描述（由申请人提供）：在本项目中，我们将评价8种新型99 mTc（III）配合物[99 mTc（S-R）（CDO）（CDOH）2B-Me]（R = P1 - P24）作为SPECT放射性示踪剂心肌灌注成像。将使用Sprague-Dawley（SD）大鼠评价其心脏摄取和生物分布。这些研究旨在回答以下三个基本问题：（1）它们是否能够在心脏中定位和保留（高心脏摄取和长心肌保留）？(2)PEG组对99 mTc放射性示踪剂的心脏摄取和肝脏清除有何影响？(3)哪种放射性示踪剂对心脏摄取、心肌保留和心脏/肝脏比最好？本项目的主要目的是增加心肌保留和最大限度地减少肝脏摄取的新型99 mTc（III）放射性示踪剂，同时保持其高心脏摄取。假设与策略：我们假设硫醇盐能够通过阻止它们在体内的水解来增加它们的99 mTc（III）络合物[99 mTc（S-R）（CDO）（CDOH）2BMe]（R = P1 - P24）的心肌保留，因为硫醇盐-S与Tc（III）形成比Cl更强的键。我们还假设聚醚基团将增加99 mTc（III）络合物的心肌保留和肝脏清除，因为已经确定PEG基团可以增加治疗剂的血液保留时间，并且我们的研究清楚地表明聚醚基团能够改善阳离子99 mTc放射性示踪剂的肝脏清除。为了验证这些假设，我们制定了一个两步策略。在第一步中，我们将制备配合物[99 mTc（S-R）（CDO）（CDOH）2B-Me]（R = P1 - P24）。不同的R基团用于平衡它们的亲脂性，使得它们的心脏摄取和T/B比率可以以系统的方式优化。在第二步中，我们将评估它们在SD大鼠中的心脏摄取和生物分布。出于比较目的，99 mTc-替硼肟将始终用作对照品。这些研究的结果将使我们能够选择一个最佳的候选人在未来的进一步评估。临床意义目前，超过7000万美国人患有心血管疾病，每年导致超过910，000人死亡。CAD患者的快速和准确的诊断是非常可取的，以便可以给出适当的治疗方案。该项目的资助和成功完成可能会导致新的99 mTc放射性示踪剂具有非常高的首过提取分数，心脏/肝脏比远远优于99 mTc-Teboroxime。高心脏摄取和更好的心脏/肝脏比将允许早期采集图像，并通过减少肝脏放射性散射来提高图像质量。高首过提取和血流速率与放射性示踪剂心肌摄取之间的线性关系将允许更好地检测冠状动脉疾病的存在和程度，以及更精确地描绘心肌灌注缺陷，这在管理已知或疑似CAD患者以及评估未来心脏事件（特别是心肌梗死和死亡）的风险方面具有相当大的益处。